This application requests renewed funding for a K24 Mid-Career Award for Patient Oriented Research (FOR) for Sonia Caprio, M.D. During the previous cycle of this award, Dr. Caprio and her group used the model of impaired glucose tolerance to study early changes in insulin resistance and beta-cell function in the development of T2DM in obese children and adolescents. Using epidemiological and physiological approaches, we revealed: 1) a high prevalence of IGT and the metabolic syndrome in obese children and adolescents, 2) adolescents with IGT have profound peripheral insulin resistance associated with increased intramyocellular lipid accumulation and visceral fat, beta-cell dysfunction and low adiponectin levels, 3) in only 2 years, 25% of the obese youth with IGT progressed to T2DM. The goal of this proposal is to provide continued support for Dr. Caprio so that a greater proportion of her time can be devoted to developing research projects and mentoring clinical scientists. The studies that are involved in this proposal include mechanistic studies that utilize rosiglitazone to assess whether the dysfunctional fat cells can be converted to healthy adipocytes and whether the abnormal pattern of fat distribution can be reversed in obese adolescents with IGT, thereby leading to enhanced muscle insulin sensitivity and improved beta-cell function (R01 HD 47878). Other studies are proposed to characterize the metabolic phenotype of obese children and adolescents with non-alcoholic fatty liver disease (NAFLD) and compare them to weightmatched controls. A new longitudinal study has been added to determine the relationship between adiposity and inflammatory markers and their contribution to insulin resistance and the metabolic syndrome in an established well-characterized cohort of obese youth. This longitudinal analysis will help to define the factors responsible for the development of the metabolic syndrome in obese youth. The impact of inflammatory markers on the progression of the metabolic syndrome will be examined. My productive, ongoing NIHfunded clinical research program and 15 years of experience in patient-oriented research make me wellsuited to receive continuation of the K24 award. The additional funds would allow me to raise my effort of NIH research support commensurate with the amount of time I currently commit to patient-oriented research and mentoring, and would allow me to continue to expand in both these areas.